Vitamin E intermediates and a process for their manufacture and conversion into vitamin E

ABSTRACT

Novel methyl carbinol derivatives of Vitamin E and a method for their manufacture.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 07/341,889 filed Apr. 24,1989, now U.S. Pat. No. 4,996,375, which in turn is a divisionalapplication of Ser. No. 07/119,879 filed Nov. 12, 1987, now U.S. Pat.No. 4,851,585.

BACKGROUND OF THE INVENTION

The present invention is concerned with a novel process for themanufacture of tert. methylcarbinol derivatives, which are suitable asintermediates for the manufacture of d-α-tocopherol (natural vitamin E),and with a process for the manufacture of d-α-tocopherol itself. Theinvention is also concerned with novel intermediates in this process.

Several processes for the manufacture of natural vitamin E are known,but they are only of limited interest from the industrial point of view.Accordingly, natural vitamin E has hitherto been extracted almostexclusively from natural sources.

There accordingly exists a need for an industrially realizable processin accordance with which natural vitamin E can be obtained in good yieldand with high optical purity. This is now possible by means of theprocess in accordance with the invention.

SUMMARY OF THE INVENTION

The instant invention comprises a process for the manufacture oftert.methylcarbinol derivatives which are suitable as intermediates forthe manufacture of d-α-tocopherol.

The instant invention also comprises a process for the manufacture ofd-α-tocopherol.

The instant invention also comprises the novel intermediates in themanufacture of d-α-tocopherol.

DETAILED DESCRIPTION

This process comprises reacting a compound of the general formula##STR1## wherein R represents a leaving group, with a metal-organiccompound of the general formula ##STR2## wherein R¹ represents anoptionally substituted metal atom and R² signifies a residue of theformula ##STR3## --CH(OR³)₂ or --CH₂ R⁴ in which R³ represents loweralkyl and R⁴ represents halogen or an ether group,

and, if desired, converting a thus-obtained compound of the formula##STR4## wherein R² has the above significance, into a compound of thegeneral formula ##STR5## wherein R and R² have the above significance,if desired, converting a thus-obtained compound of general formula IVinto an epoxide of the formula ##STR6## wherein R² has the abovesignificance, if desired, reacting an epoxide of formula V with acompound of the general formula ##STR7## wherein R⁵ represents an etherprotecting group or one equivalent of an alkali metal or alkaline earthmetal,

and, if desired, converting a thus-obtained compound of the generalformula ##STR8## wherein R⁵ has the above significance, intod-α-tocopherol.

The term "leaving group" signifies in the scope of the present inventionnot only halogen such as chlorine, bromine or iodine, but also sulphonicacid ester such as tosylate or mesylate as well as carboxylic acid estersuch as acetate, benzoate and the like.

As metal atoms there come into consideration in the scope of the presentinvention the metals which are usually used for metal-organic couplingreactions, such as, for example, alkali metals or alkaline earth metalssuch as lithium, sodium, potassium, magnesium, as well as transitionmetals such as copper, titanium, zinc, mercury and the like, withmagnesium being preferred. As substituents on the metal atom there comeinto consideration, in particular, halogen such as chlorine, bromine oriodine as well as lower alkoxy groups with 1 to 6 carbon atoms.

The term "lower alkyl" signifies in the scope of the present inventionalkyl groups with 1 to 6 carbon atoms, which can be straight-chain orbranched, such as, for example, methyl, ethyl, propyl, butyl, pentyl,hexyl etc. The term "lower alkoxy" signifies groups in which the alkylresidue has the foregoing significance. The term "halogen" signifies, inparticular, fluorine, chlorine and bromine, with chlorine and brominebeing preferred.

The term "ether protecting group" signifies in the scope of the presentinvention not only groups which are cleavable by hydrolysis such as, forexample, the silyl group or alkoxymethyl groups, for example themethoxymethyl group, or also the tetrahydropyranyl group, but alsogroups which are cleavable oxidatively such as, for example, C₁ -C₆-alkyl ether groups. Alternatively, the protection of the phenolichydroxyl groups can also be achieved by an appropriate metal saltgrouping, namely by an alkali metal salt or alkaline earth metal salt.Sodium, lithium and potassium are preferred. Furthermore, the notation "" signifies that the corresponding residue is situated above the planeof the molecule, while the notation " " signifies that the correspondingresidue is situated below the plane of the molecule.

The reaction of a compound of general formula I with a compound ofgeneral formula II is conveniently effected by firstly reacting acompound of formula I in an inert organic solvent with an alkali metalhydride or alkaline earth metal hydride until the hydrogen evolution hasfinished and subsequently adding a compound of formula II.

As alkali metal hydrides or alkaline earth metal hydrides there can beused in the scope of the present invention especially lithium, sodium orpotassium hydride or calcium hydride. The temperature and the pressureare of no critical significance in this reaction. The reaction ispreferably effected at room temperature and normal pressure.

The conversion of a compound of general formula III into a compound ofgeneral formula IV can be effected in a manner known per se. Thisconversion is conveniently effected by reaction with acid halides orimidazolides in inert organic solvents, preferably with the addition ofan organic base such tert. amines. e.g. pyridine, triethylamine etc.

The conversion of a compound of general formula IV into to an epoxide ofgeneral formula V can be effected in a manner known per se, i.e. bytreatment with a base. Both inorganic bases and organic bases aresuitable for use as bases. However, inorganic bases such as, inparticular, sodium hydroxide or potassium hydroxide or also sodiumhydride or calcium hydride and the like are preferred.

The reaction of an epoxide of general formula V with a compound ofgeneral formula VI is conveniently effected either by reacting acompound of formula VI, after the addition of a suitable alkali alkyl oralkaline earth alkyl compound, in an inert organic solvent with theepoxide or heating a compound of general formula VI in an inert organicsolvent with the epoxide in the presence of an alkali metal hydride oralkaline earth metal hydride and a phase transfer catalyst, convenientlyto a temperature of about 60° C. to about the reflux temperature of thereaction mixture and, if desired, under pressure.

As the inert organic solvent there can be used in the scope of thepresent invention the solvents which are usually used in metal-organicreactions. Examples of such solvents are ethers, especially cyclicethers such as tetrahydrofuran or dioxan or also mixtures of theseethers with aliphatic hydrocarbons such as, in particular, pentane,hexane and the like.

The phase transfer catalysts which are required in the scope of thepresent invention are the usually used known phase transfer catalystssuch as e.g. quaternary ammonium salts, crown ethers or also polyethersand the like. As alkali alkyl or alkaline earth alkyl compounds therecome into consideration in the scope of the present invention e.g.tert.butyllithium, C₁ -C₆ -alkyl-potassium, C₁ -C₆ -alkylsodium,Grignard compounds and the like.

The compounds of general formula VII in which R² represents the residueof the formula ##STR9## which are obtained according to the process inaccordance with the invention, are known and can be converted intod-α-tocopherol in a known manner.

On the other hand, those compounds of formula VII in which R² signifiesa residue of the formula --CH(OR³)₂ or --CH₂ R⁴ are novel and are alsoan object of the present invention. The conversion of such a compoundinto a compound of formula VII in which R² represents the residue##STR10## can be effected in a manner known per se, e.g. by reactionwith a phosphonium salt of the formula ##STR11## wherein R⁶ represents aphenyl residue, under the conditions which are usual for Wittigreactions or also for other metal-organic reactions. Alternatively, thechromane ring in a compound of formula VII in which R² represents aresidue of the formula --CH(OR³)₂ or --CH₂ R⁴ can firstly be closed in amanner known per se, e.g. by acidic hydrolysis or by oxidation andsubsequent reductive cyclization. Thereupon, the side-chain in athus-obtained compound can be lengthened in analogy to the foregoing.

The compounds of formulae I and II which are used as starting materialsin the process in accordance with the invention are known compounds oranalogues of known compounds which can be prepared in an analogousmanner to the preparation of the known compounds.

The present invention will be further described in connection with thefollowing examples which are set forth for the purpose of illustrationonly.

EXAMPLE 1

367 mg (3 mmol) of (2S)-3-chloro-2-methyl-1,2-propanediol were dissolvedin 5 ml of dry tetrayhydrofuran and left to react at room temperaturewith 100 mg (7.2 mmol) of sodium hydride (55-60%) until the evolution ofgas had finished. 350 mg of potassium tert.-butylate were added to theresulting thick suspension. Thereupon, 2.9 mmol of(3RS,7RS)-3,7,11-trimethyldodecylmagnesium bromide were added and themixture was stirred at room temperature for 16 hours. 50 ml of waterwere subsequently added and the mixture was extracted with ether. Theorganic phases were dried over sodium sulphate and concentrated. Therewas obtained 0.81 g (96%) of(2R,6RS,10ORS)-2,6,10,14-tetramethyl-1,2-pentadecanediol with

[α]_(D) ²⁰ =+1.35° (c=1.5% in CHC1₃).

The (2S)-3-chloro-2-methyl-1,2-propanediol used as the starting materialwas prepared as follows:

7.9 ml (26 mmol) of tetraisopropyl orthotitanate, 150 mg (2.5 mmol) ofcalcium hydride, 150 mg (2.5 mmol) of silica gel and 5 ml (30 mmol) ofdibutyl L-tartrate were left to stand at -18° C. for 10 minutes in 150ml of methylene chloride. Then, 1.6 ml (25 mmol) of beta-methallylalcohol and 7 ml (50 mmol) of cumene hydroperoxide (66% in cumene) wereadded dropwise and the mixture was left to stand at -18° C. for 16hours. Thereupon, 300 ml of diethyl ether and 50 ml (0.35 mol) of sodiumhydroxide solution (28%) were added and the mixture was stirred at roomtemperature for 1.5 hours. The mixture was then extracted with ether,the organic phases were treated with 20.3 g (0.1 mol) of magnesiumchloride and stirred at room temperature for 16 hours. The mixture wassubsequently filtered, the filtrate was concentrated and cumene andcumene alcohol were distilled off with steam. The residue wasconcentrated and there were obtained 2.47 g of(2S)-3-chloro-2-methyl-1,2-propanediol as a colourless oil with [α]_(D)²⁰ =+5.4° (c=3% in CHCl₃) and an optical purity of above 98% (e.e.)according to gas-chromatographical methods (Mosher derivative). In ananalogous way, compound III with R² =CH(OCH₃)₂ or R² =CH₂ --O--CH₂ --Phcan be obtained by using the corresponding Grignard-reagent II (R¹=MgBr).

EXAMPLE 2

0.81 g (2.8 mmol) of(2R,6RS,10RS)-2,6,10,14-tetra-methyl-1,2-pentadecanediol and 540 mg (2.9mmol) of tosyl chloride were left to react at room temperature for 16hours in 2 ml of pyridine. The mixture was then treated with 50 ml of INhydrochloric acid and extracted three times with 50 ml of diethyl ethereach time. The organic phases were dried over sodium sulphate andconcentrated. There were obtained 1.22 g (99%) of(2R,6RS,10RS)-1-tosyloxy-2,6,10,14-tetramethyl-3-pentadecanol with[α]_(D) ²⁰ =-1.48° (c=2% in CHCl₃).

EXAMPLE 3

760 mg (2.9 mmol) of 2,5-di-(methoxymethoxy)-1,3,4,6-tetramethylbenzenewere dissolved in 20 ml of tetrahydrofuran, treated at room temperaturewith 330 mg of potassium tert.butylate and subsequently with 2 ml (3.2mmol) of n-butyllithium and left to react for 1 hour. The mixture wasthen left to react at room temperature for 16 hours with(2R,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethyl-pentadecane, prepared from1.22 g of (2R,6RS, 10RS)-1-tosyloxy-2,6,10,14-tetramethyl-3-pentadecanoland 500 mg (3.1 mmol) of sodium hydride in 30 ml of tetrahydrofuran.Thereupon, 10 ml of HBr (30%) in 50 ml of methanol were added and themixture was left to stand for 24 hours. Subsequently, methanol was addedand the mixture was then concentrated to dryness. The residue wasfiltered over silica gel with toluene and there were obtained 1.1 g(88%) of (2R,4'RS,8'RS)-α-tocopherol.

EXAMPLE 4

1.52 g (3.3 mmol) of(2R,6RS,10RS)-2,6,10,14-tetramethyl-1-tosyloxy-2-pentadecanol weredissolved in 20 ml of ethanol. 2 ml of sodium hydroxide solution (50%)were then added and the mixture was stirred for 16 hours. Subsequently,50 ml of water were added and the mixture was stirred up with HYFLO. Thesuspension was then filtered and washed with water. The residue wastriturated with diethyl ether, dried over sodium sulphate, filtered andconcentrated. There was obtained(2R,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane with [α]_(D) ²⁰=-0.21° (c=2% in CHCl₃).

EXAMPLE 5

1.8 g (9 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene weredissolved in 100 ml of tetrahydrofuran, treated with 1 g (9 mmol) ofpotassium tert.butylate and subsquently 6 ml (9.5 mmol) ofn-butyllithium (1.6 molar) were added dropwise at room temperature.Thereafter, the mixture was stirred at room temperature for 30 minutes,treated dropwise with 2.7 g (9 mmol) of (2RS,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane and stirred at roomtemperature for 16 hours. Thereupon, HYFLO and 200 ml of water wereadded, the mixture was then filtered and washed with water. The residuewas stirred up with diethyl ether and sodium sulphate, filtered, washedwith diethyl ether and concentrated. There were obtained 3.8 g of(3RS,7RS,11RS)-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3,7,11,15-tetramethyl-3-hexadecanol.

EXAMPLE 6

10 g (66.7 mmol) of tetramethylhydroquinone are dissolved in 100 ml ofdry tetrahydrofuran, 4 g (139 mmol) of sodium hydride (80% in mineraloil) are added thereto at room temperature, 45 ml of butyllithium (1.6molar in hexane) are subsequently added dropwise and the mixture isstirred for 1 hour. 10 g (44.3 mmol) of 1,2-epoxy-2,6,10,14-tetramethylpentadecane are now added dropwise; the mixture isleft to react for 12 hours while stirring. 100 ml of 1N methanolichydrochloric acid are added and the mixture is stirred at 50° C. for 2hours. The mixture is subsequently concentrated at 50° C. and theresidue is chromatographed on silica gel with toluene, whereby there areobtained 14.9 g (75%) of α-tocopherol.

We claim:
 1. A compound of the formula ##STR12## wherein R is asulphonic acid ester leaving group and R² is ##STR13## --CH(OR³)₂ or--CH₂ R⁴ in which R³ represents lower alkyl and R⁴ represents halogen.2. The compound of claim 1 wherein R is tosyloxy.
 3. The compound ofclaim 2 wherein R² is ##STR14##
 4. The compound of claim 1 wherein R² is--CH(OR³)₂.
 5. The compound of claim 4 wherein R is tosyloxy.
 6. Thecompound of claim 1 wherein R² is --CH₂ R⁴.
 7. The compound of claim 6wherein R is tosyloxy.